Persistent Helicobacter pylori colonization results in diseases such as gastritis, ulcer disease, gastric carcinoma, and iron deficiency anemia (IDA). Given the large environmental fluctuations that H. pylori experiences in the stomach, the bacterium must be adept at regulating gene expression as a means to adapt and survive in this niche. Furthermore, H. pylori utilizes environmental signals as a means to control gene expression. For example, the bacterium utilizes iron availability as signal to regulate expression of colonization and virulence genes. On the regulatory front, the Ferric Uptake Regulator (Fur) is known to function as an iron co-factored regulatory protein. We have shown that Fur-mediated regulation is crucial for H. pylori colonization and disease; Fur mutant strains show altered dynamics of colonization in the gerbil model of infection as well as significant attenuation in development of inflammation and gastric cancer. Our preliminary studies suggest that the effect on disease may be due to a role for Fur in activation of expression of cagA, which encodes a type IV secreted effector protein that is crucial for cancer development. Herein, we propose to characterize the process of Fur-mediated activation of expression of cagA and to examine expression and delivery of CagA in vivo. We predict that our work will shed significant insight into the process by which expression of this key virulence factor is mediated in H. pylori and help to determine the role of environmental signaling in infection and ultimate disease development. These studies will fill a fundamental gap in our knowledge and could provide potential new therapeutic targets for H. pylori.